Thallium (I) Penicillanates

ABSTRACT

Thallium (I) penicillanates are uniquely adaptable for synthetic production of penicillanic acid anhydrides of mixed and symmetrical derivation. The penicillanic acid anhydrides are valuable as intermediates in the production of known penicillin derivatives as well as in the repository antibiotic administration.

Entitled States Patent 1191 Sellsted et al.

[451 Jan. 28, 1975 1 THALLIUM (l) PENICILLANATES [75] Inventors: John H. Sellsted, King of Prussia;

Daniel M. Teller, Devon, both of Pa.

[73] Assignee: American Home Products Corporation. New York NY.

[22] Filed: Oct. 27, 1972 [21] Appl. No.: 301,702

FOREIGN PATENTS OR APPLICATIONS 73,100 8/1953 Netherlands 260/2391 OTHER PUBLICATIONS Taylor et al., Journal of American Chem. Soc, 90, p. 2422-2423, 1968 Primary l;'.\'aminerNicholas S. Rizzo Aszvislunl I;.\amitwr--Mary C. Vaughn Attorney Agent. or Firm-Richard K. Jackson [57] ABSTRACT Thallium (l) penicillanates are uniquely adaptable for synthetic production of penicillanic acid anhydridcs of mixed and symmetrical derivation. The penicillanic acid anhydrides are valuable as intermediates in the production of known penicillin derivatives well as in the repository antibiotic administration.

2 Claims, N0 Drawings a 2 THALLIUM (l) PENICILLANATES thallium (l) salts of penicillanic acids and a process for BACKGROUND OF THE INVENTION ztihjgdlfigelsn the production of mixed and symmetrical The reaction of thallium (l) salts of carboxylic acids More specifically, the present invention provides with acyl halides in the production of both mixed and 5 compounds of the formula: symmetrical anhydrides is disclosed by Taylor et al.,

J.A.C.S.. 90. pp. 2422-2423 (1968). The production R and use of mixed anhydrides of penicillanic acids is disi closed by Cooper in U.S. 2,577,699.

BRIEF DESCRIPTION OF THE INVENTION In accordance with this invention there is provided in which R is selected from the group consisting of:

R2 n) F- 0 NH i l \S err-com ocn-c NH- I N11,}: 1L? 1' Q TH-fi-NH; no-Q-cnc0NH- I 1TH O P P comrcx NH I I NH.

. 3 4 wherein and Schiff bases formed from such reactants as ethyla- R and R are selected from the group consisting of hycetoacetate and pentane-2,4-dione. drogen and lower alkoxy; R is selected from the group Within the group of thallium (I) penicillanates deconsisting of hydrogen, lower alkyl and phenyl; R and scribed above are those preferred as intermediates for R when taken separately are selected from the group 5 production of mixed anhydrides which are most desirconsisting of hydrogen and lower alkyl, and when taken able from the standpoint of production economics and together with the carbon atom to which they are atactivity. Those preferred compounds are represented tached, complete a ring selected from the group conby the preceding structural formula where R is selected sisting of cycloalkyl containing from about 4 to about from the group consisting of -CNH-(PenG) CONH a c1 1n) O OC H Gown-corm- (Pen v) -CONH- (Cloxacillin) R4 on and -CH CONH (Carbenicillin).

8 carbon atoms and piperidine; R is lower alkyl or cy- The salts described in this invention may be prepared cloalkyl of 4 to 8 carbon atoms, mesyl or 2,6- by the following reaction scheme.

CH3 R s 3 CH TlOCH CH 9 dimethoXy phenyl; a is one of the integers O and l and The anhydrides are produced from the thallous peni- P-is a commonly used, easilyremovable protecting cillanates by the following general reaction scheme.

group for an amino substituent. I in which the group R has the aforesaid meaning, R is Illustrative examples of protective groups for amino the residue of the acyl halide and X is a halogen such substituents are described by Boissonnas, Advances in as chlorine, bromine or iodine. Organic Chemistry, vol; 3, (1963) pp. 159-190; McO- Throughout this specification, the term lower alkyl is mie, ibid, pp. 203-210 273; Patchornik et al., J.A.C.S., conventionally used to encompass straight and vol. 92, pp. 6333-6335, 1970. Of those described in the branched chain alkyl groups containing from i to about prior art, the protective groups most amenable to use 7 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, in the preparation of the compounds of this invention butyl, isobutyl, pentyl, 2-ethyl propyl, hexyl, 2-propyl are of the ox'ycarbonyl type, represented more specifipropyl, and the like. Similarly, the term lower alkoxy is cally by the 6-nitroveratryloxycarbonyl, 2-nitrobenused to encompass straight and branched chain groups zyloxycarbonyl, 4-nitrobenzyloxycarbonyl 2,2-' containing from I to about 7 carbon atoms.

dinitrodiphenylmethyloxycarbonyl, benzyloxycarbo In the production of symmetrical anhydrides of a nyl, t-butyloxycarbonyl and trichloroethoxycarbonyl penicillanic acid, an alternate route to that of the reacgroup; the phenylsulfenyl type, represented by the 0- tion ofthallium penicillanate with the same penicillanic nitrophenylsulfenyl and p-methoxy-oacid halide, involves the reaction of the thallium (l) nitrophenysulfenyl groups; the triphenylmethyl group penicillanate with thionyl chloride to produce the inter- 6 mediate diacyl sulfite which spontaneously loses sulfur ence of diethyl ether to pH 2. The layers are separated dioxide to afford the desired symmetrical anhydride. and the aqueous layer extracted again with diethyl The following equation exemplifies this reaction: ether. The ether is washed with brine and dried with f 00 1 1 co so R --h 1 a CO 0 O l l in which R has the definition previously given. MgSO,. Thallium ethoxide (24.9 g, 0.1 mole) is slowly In the production of thallium penicillanates, applidripped into the ether solution after filtering off the cants have surprisingly discovered that the nucleophil- MgSO The precipitate is collected and washed with lic properties general ascribed to metal alkoxides, are dlethyl ether, and dried at in not sufficient in thallium (I) alkoxides (thallium ethox- Elemental Analysis for CIBHHNZO4STI ide) to open the B-lactam moiety of the penicillanic Calculated: 35-73; H, 319; 520; i acid structure. Thus, unexpectedly, thallium alkoxides Found: 36-43; 3'47? 7'22; may be used to produce thallium penicillanates without destruction of the heterocyclic nucleus to anuntoward EXAMPLE degree' During the reaction of the thallium penicillanate with 6'(ZPhenoxyacetafnldolpefllclllfmlc acld anhydnde an acyl halide, applicants have found that the thallium PmhC chloride salt produced is readily separable from the anhydride product, thereby removing from the pharma- A Suspension of thallium Penicillin V "1018,

ceutical preparation the presence of thallium salts, 8) in diethyl ether lf Containing R y known to be extremely toxic biologically. Thus, it is Chloride mole L20 8 surfed under mll'ogen preferred, to assist in the removal of thallium salts dur- 19 P The mlxtuge is filtered and l i5 ing the preparation of a symmetrical or mixed anhy- SIFIPPBQ m ,Vacuo 30 The Solid residue drides, to employ a solvent in which the produced thah rated with diethyl ether giving 1.53 g of colorless product; mp. ll9-l2lC.; homogeneous on thin layer 40 chromatography.

Elemental Analysis for c,,H,,N,o,s

Calculated: C, 58.05; H, 6.05; N, 6.45; S, 7.37. Found: C, 57.20; H, 6.33; N, 6.46; S, 7.78.

lium halide is insoluble. The preferred solvents are ethers such as diethyl ether or diisopropyl ether, while in general, the lower aliphatic ethers are acceptable reaction media.

The following specific examples presented by way of illustration, are not to be interpreted as limitations upon the invention claimed.

EXAMPLE I Thallium Penicillin V Penicillin V acid (3.50 g, 0.01 mole) is dissolved in OCH CONH 15 ml tetrahydrofuran and thallium ethoxide (2.49 g, 2 I

What is claimed is:

l. Thecompound which is 0.01 mole) dissolved in 5 ml. of tetrahydrofuran is added over 10 minutes, giving an orange precipitate 2 that changed to white. The mixture is filtered and the solid is washed with cold tetrahydrofuran and diethyl ether, giving 2.6 g, mp. 197C. (dec). The solid is re- T o d whi h i crystallized from isopropanol-water, mp. 189C. (dec).

Elemental Analysis for C H N O SU Calculated: C, 36.70; H, 3.07; N, 5.06; S, 5.79. 3 Found: C, 35.49; H, 3.16; N, 5.07; S, 5.40; H O, 2.40. H CONH *f I EXAMPLE 2 4"' -N CO Tl Thallium Penicillin G Potassium penicillin G (41.0 g, 0.1 mole) is dissolved in 500 ml cold water and acidified at 0.5C. in the presiii =i 

2. THE COMPOUND WHICH IS 